Acute kidney injury (AKI) is a common and serious condition recognized in nearly all fields of medical practice. It is characterized as a rapid and intensive decline of renal function associated with series of clinical syndrome which account for high morbidity and mortality (Ronco et al. (2007) Improving outcomes from acute kidney injury (AKI): Report on an initiative. Int J Artif Organs 30: 373-376), Webb S et a., (2007) ARF, ATN or AKI? It's now acute kidney injury. Anaesth Intensive Care 35: 843-844). The mortality rate in hospital intensive care units ranges from 40% to 80%. Furthermore, Acute kidney injury (AKI) predisposes patients to the development of both chronic kidney disease and end-stage renal failure. AKI is characterized by a rapid decline in kidney function, often triggered by an ischemic or toxic insult. This clinical syndrome is associated with substantial short-term morbidity, mortality, and cost, but it had previously been assumed that patients surviving the episode made a full renal recovery. However, AKI is now appreciated to be markedly associated with increased risk of future chronic kidney disease (CKD), end-stage renal disease (ESRD) (Ishani A, et al., J Am Soc Nephrol. 2009; 20(1):223-228.; Wald R, et al., JAMA. 2009; 302(11):1179-1185.), and long-term mortality (Lafrance J P, Miller D R, J Am Soc Nephrol. 2010; 21(2):345-352.). The population rate of AKI is increasing at greater than 7% per year, and some estimates indicate that the incidence of AKI-related ESRD is equal to the incidence of ESRD from diabetes. The mechanisms that might explain the link between AKI and future CKD/ESRD are poorly understood, but peritubular capillary loss, a known consequence of AKI (Basile D P, et al., Am J Physiol Renal Physiol. 2001; 281 (5):F887-F899.), is proposed to lead to chronic hypoxia and later development of tubulointerstitial fibrosis and CKD (Kang D H, et al., J Am Soc Nephrol. 2002; 13(3):806-816; Nangaku M., J Am Soc Nephrol. 2006; 17(1):17-25). How chronic ischemia might trigger parenchymal loss at a molecular level is unresolved.
Acute kidney injury (AKI) predisposes patients to the development of both chronic kidney disease and end-stage renal failure, but the molecular details underlying this important clinical association remain obscure. AKI is characterized by a rapid decline in kidney function, often triggered by an ischemic or toxic insult. This clinical syndrome is associated with substantial short-term morbidity, mortality, and cost, but it had previously been assumed that patients surviving the episode made a full renal recovery. However, AKI is now appreciated to be markedly associated with increased risk of future chronic kidney disease (CKD), end-stage renal disease (ESRD) (Ishani A, et al., J Am Soc Nephrol. 2009; 20(1):223-228.; Wald R, et al., JAMA. 2009; 302(11):1179-1185.), and long-term mortality (Lafrance J P, Miller D R, J Am Soc Nephrol. 2010; 21(2):345-352).
Furthermore, diabetic nephropathy (DN) is the leading cause of end-stage renal disease (ESRD) in the United States and is epidemic worldwide. It is estimated that 33% of the US adult population will have diabetes by 2050. While proteinuria in diabetes has generally been attributed to abnormalities in the glomerulus, tubulointerstitial disease is the best indicator of functional progression of disease (Bonventre, J. V. Semin Nephrol 32, 452-462 (2012); Vallon, V., Am J Physiol Regul Integr Comp Physiol 300, R1009-1022 (2011); Tang, S. C. & Lai, K. N., Nephrol Dial Transplant 27, 3049-3056 (2012); Mauer, S. M., et al., J Clin Invest 74, 1143-1155 (1984); White, K. E. & Bilous, R. W., J Am Soc Nephrol 11, 1667-1673 (2000)). Tubular abnormalities may precede glomerular pathology early in DN (Jefferson, J. A., et al., Kidney Int 74, 22-36 (2008)). Pathological mechanisms that may initiate and/or mediate tubular epithelial injury and degeneration in DN remain, however, poorly understood. While current therapies that target hemodynamics in the glomerulus can slow disease progression, in most patients, DN is progressive, resulting in chronic kidney disease (CKD) and ESRD in approximately 30% of patients. A better understanding of the pathobiology and identification of novel therapeutic targets for the treatment of DN are desperately needed.
Early diagnosis and intervention of AKI and subjects at risk of ESRD could effectively prevent the occurrence of the outcome. Despite the advanced progress made in etiology and pathology of AKI, the clinical detection and diagnosis was still in controversy. Nowadays, the most widely used and commonly accepted clinical standard for the definition and diagnosis of AKI usually relies on the increase of serum creatinine or decrease of urine output which was proposed by both AKIN (acute kidney injury network), RIFLE (risk, injury, failure, loss, and ESRD) [Lattanzio et al., (2009) Acute kidney injury: new concepts in definition, diagnosis, pathophysiology, and treatment. J Am Osteopath Assoc 109: 13-19. 4)], and Kidney Disease Improving Global Outcomes (KDIGO) criteria. Unfortunately, due to the poor sensitivity and specificity and 48 h-72 h time needs, serum creatinine was incapable to comprehensively reflect the time and type of renal injury. Moreover, serum creatinine was also affected by some other factors, such as age, acute and chronic renal failure. These studies suggested that more accurate and efficient measure for AKI diagnosis was urgently required (Slocum J L, et al., (2012) Marking renal injury: can we move beyond serum creatinine? Transl Res 159: 277-289).
The lack of sensitive and specific kidney injury biomarkers greatly impedes the development of therapeutic strategies to improve outcomes of AKI. The traditional blood (creatinine, blood urea nitrogen) and urine markers of kidney injury (casts, fractional excretion of sodium, urinary concentrating ability), that have been used for decades in clinical studies for diagnosis and prognosis of AKI, are insensitive, nonspecific, and do not directly reflect injury to kidney cells. Outside of the clinical setting, the lack of specific AKI biomarkers has impeded the development of drugs and therapies that may improve the devastating outcomes of AKI. There is currently no plasma biomarker that specifically reflects kidney proximal tubule injury with high specificity.
Lines of evidence showed that urinary NGAL, IL-18, Cys-C, KIM-1 and some other candidate molecules were believed as potential urinary markers to diagnosis of AKI (Adiyanti S S (2012) Acute Kidney Injury (AKI) biomarker. Acta Med Indones 44: 246-255; Edelstein C L (2008) Biomarkers of acute kidney injury. Adv Chronic Kidney Dis 15: 222-234. But until now, none of them are currently established well enough to replace serum creatinine as a marker of renal function. Among these markers, growing evidence showed that KIM-1 performed significantly better in early detection of AKI than others, especially within 24 hours, well before serum creatinine increase, which made it possible to conduct prevention or treatment strategies at a very early stage of AKI (Liangos O, (2009) Comparative analysis of urinary biomarkers for early detection of acute kidney injury following cardiopulmonary bypass. Biomarkers 14: 423-431; Han W K, et al. (2008) Urinary biomarkers in the early diagnosis of acute kidney injury. Kidney Int 73: 863-869).
Kidney Injury Molecule-1 (KIM-1) is highly upregulated in dedifferentiated proximal tubular cells following kidney injury, and the ectodomain of KIM-1 is shed into the lumen and can be used as a urinary biomarker of kidney injury. Previous reports had proved KIM-1 in rat model to be an outstanding indicator of kidney proximal tubule injury, much better than serum creatinine (Ichimura T, (1998). KIM-1 is a putative epithelial cell adhesion molecule containing a novel immunoglobulin domain, and is markedly up-regulated in renal cells after injury. J Biol Chem 273: 4135-414213). Urinary KIM-1 levels are strongly related to tubular KIM-1 expression in experimental and in human renal disease [Waanders F, (2010) Kidney injury molecule-1 in renal disease. J Pathol 220: 7-1612]. Studies in humans indicated that urinary KIM-1 was sensitive and specific marker of injury as well as predictors of outcome [Bonventre J V (2008) Kidney Injury Molecule-1 (KIM-1): a specific and sensitive biomarker of kidney injury. Scand J Clin Lab Invest Suppl 241: 78-83]. Recently, two systematic reviews have reported that KIM-1 was an efficient novel urinary biomarker in diagnosis of AKI within 24 hours after kidney injury [Huang Y, (2011) The clinical utility of kidney injury molecule 1 in the prediction, diagnosis and prognosis of acute kidney injury: a systematic review. Inflamm Allergy Drug Targets 10: 260-271; Coca S G, (2008) Biomarkers for the diagnosis and risk stratification of acute kidney injury: a systematic review. Kidney Int 73: 1008-1016), especially in the diagnosis of ischemic ATN (Huang Y, 2011).
However, KIM-1 as a urinary biomarker for diagnosis of AKI was determined to be only 74% sensitive (Shao et al., (2014); PLOS, Diagnostic value of urinary kidney-injury molecule-1 for acute kidney injury: A Meta Analysis. 9(1); e84131)) when AKI was defined by an increase in serum creatinine. Furthermore, while spot urinary KIM-1 concentration normalized to urinary creatinine concentration is very attractive as a urinary biomarker given the stability of KIM-1 and the easy accessibility of urine specimens, there can be significant variability of urinary excretion over time in patients with AKI such that a spot collection may not be ideal under all circumstances (Waikar et al., (2010). Normalization of urinary biomarkers to creatinine during changes in glomerular filtration rate. Kidney Int 78(5):486-494). Thus, for urinary biomarkers to accurately detect kidney injury, it would be ideal to assay the biomarker from timed collection of urine samples in order to estimate renal excretion rate; however, this is not practical for routine clinical care. Hence, there remains an urgent need for more reliable sensitive biomarkers for detecting and monitoring kidney injury and AKI.
Another type of injury to the kidney is kidney or renal cancer. Kidney cancer is a heterogeneous disease consisting of various subtypes with diverse generic, biochemical and morphologic features. Renal cell carcinoma (RCC) accounts for 2-3% of adult malignancies and its incidence is increasing. RCC is not a uniform disease and is subdivided into clear cell, papillary, chromophobe and oncocytoma. The most common histological subtype of RCC is conventional RCC (also referred to as clear cell RCC or ccRCC), which accounts for 70-80% of all RCC cases. Based on morphological features defined in the WHO International Histological classification of Kidney Tumors, RCC can be divided into clear cell (conventional or ccRCC) (80%), papillary RCC (chromophil) (10-15%), chromophobe RCC (5%), collecting duct RCC (<1%) and unclassified RCC (<2%) subtypes. Many patients with von Hippel Lindau (VHL) disease, an autosomal dominant genetic disorder of inherited predisposition to RCC, also develop conventional RCC and studies on this familial disease facilitated the identification of the VHL tumor suppressor gene (Latif et al., Science, 1993; 260; 1317-1320).
The incidence of renal cell carcinoma (RCC) has steadily risen in the United States since 1970 and is currently estimated at approximately 51,000 cases per year. This increase has been observed across gender and race, increasing among black males and females by 3.9% and 4.3% per year, and white males and females by 2.3% and 3.1% per year, respectively. Typically, kidney organ confined RCC is treated with surgery and the five-year survival rate for patients presenting with Stage I disease is 95%, while the survival rate for patients with Stage II and III RCC is decreased to 70-80% and 40-60%, respectively. It is therefore reasonable to assume that early disease detection would improve overall survival in RCC patients.
RCC is a histological diverse disease, with variable and often unpredictable clinical behavior. The prognosis worsens dramatically with the onset of clinical metastasis and current regimens of systematic therapy yield only modest benefits for metastatic RCC. However, targeted therapy has opened a new set of possibilities and questions in RCC treatment. Tumor response by classical imaging criteria fails to reflect changes in tumor vessel density, tumor viability, or correlate with disease progression or even overall survival. The availability of biomarkers that reflect disease progression and severity as well as activity may therefore help guide therapy. Biomarkers that serve as surrogate markers of tumor response will expedite a large number of clinical trials in which kinase inhibitor are used in combination in patients both pre and post surgery. Treatment of patients with minimal residual disease may prove, now that effective therapies are available, to be a better approach than treatment following clinical detection. Adjuvant trials may target patients with biomarker-detected minimal residual disease after nephrectomy for the primary tumor.
Surgical resection is the mainstay of therapy for patients with localized primary tumors. However, new therapies are desperately needed for metastatic RCC, which is poorly responsive to chemotherapy and radiotherapy. Biomarkers could potentially be used to identify high-risk patients with localized RCC for early systemic therapy. Refining prognostic systems to more accurately predict patient outcomes and thereby guide more effective treatment decisions is an ongoing process. To date, key prognostic factors identified include TNM staging, tumor grade, functional status, and various biochemical assessments. Integrated prognostic systems combine clinical and pathological data in order to stratify patients and improve prognostic power. Additional biomarkers are likely to further increase prediction accuracy. Currently, there is no validated biomarker for renal cell cancer (RCC) such as PSA for prostate and CA125 for breast cancer. Currently there is no FDA approved marker for diagnosis of renal cell carcinoma.
Biomarker(s) that reliably correlate with disease burden or activity could be useful to detect disease before clinical signs and symptoms are apparent, even before there is radiological evidence of tumor growth. Such biomarkers can also be useful to guide early detection, such as techniques for detection of minimal residual disease (such as exploratory surgery or imaging), and could guide timing and choices of systemic therapy for relapsed or metastatic disease and can also be useful for the early identification of patients at need for adjuvant therapy after seemingly curative nephrectomy.
Such biomarkers could also be useful in the testing of potential therapeutic strategies for RCC. Surrogate markers of disease activity could also serve as surrogate endpoints in clinical trials and help shortening the length of a trial. Patients might avoid treatment with ineffective medications, thus preventing unnecessary side effect risks and serious complications. The may also be able to guide a physician to treat a patient with a more aggressive therapy where the level of the biomarker indicates a rapid progression of the RCC, and thus biomarkers for early diagnosis of RCC have the potential to guide therapeutic and preventive interventions, such as early administration of targeted/anti-angiogenic therapy, specialized imaging, exploratory surgery or chemoprevention trials. Unfortunately, reliable biomarkers for RCC have not been established yet.